EP0269105A2 - Dérivés du cyclohexane, préparations les contenant et leur utilisation - Google Patents

Dérivés du cyclohexane, préparations les contenant et leur utilisation Download PDF

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EP0269105A2
EP0269105A2 EP87117481A EP87117481A EP0269105A2 EP 0269105 A2 EP0269105 A2 EP 0269105A2 EP 87117481 A EP87117481 A EP 87117481A EP 87117481 A EP87117481 A EP 87117481A EP 0269105 A2 EP0269105 A2 EP 0269105A2
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Matti Sirén
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Perstorp AB
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Definitions

  • the present invention relates to novel derivatives of cyclo­hexane and compositions containing the same.
  • inositols The family of isomeric hexahydroxy derivatives of cyclohexane are known as inositols. There exist nine different isomers and one of these, myo-inositol, is of biological importance. Chiro­inositols and scyllo-inositols are also of natural occurence, but nothing is known of their biological role.
  • Myo-inositol is an essential nutrient for microorganisms and under special dietary condition for different animals.
  • myo-inositol such as phosphates and phospholipids.
  • Myo-inositol is found in plants principally as its hexaphosphate­ester, called phytic acid. It is further known that derivatives with a lower number of phosphate groups are formed during germination. The final products of the germination are myo-­inositol and inorganic phosphate.
  • Phospholipids are components of cell membranes.
  • One type of phospholipids is the phosphoinositides in which myo-inositol is covalently linked to derivatives of glycerol.
  • methyl ethers of myo-inositol occur in plants. The most common one is the 5-methyl ether called seqnoyitol.
  • derivatives of cyclohexane of the structural formula (I) have been produced in either acid or ester or salt form with high purity, wherein: R1, R2 and R3 independently are (a) hydrogen (b) oxygen (c) A, where A is
  • R1, R2, R3, R4, R5 and R6 can be placed in any order to each other.
  • the configuration isomers of myoinositol according to the invention are epi-, muco-, neo-, chiro-, scyllo-, allo- and cisinositol.
  • Formula (I) is not to cover compounds like inositol, inositoltriphosphate or phytic acid.
  • Alkyl with 1 to 24 carbon atoms is for example, lower alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tributyl, sec.-butyl or tert.-butyl, also n-pentyl, neopentyl, n-hexyl or n-heptyl or higher alkyl such as straight-chain or branched octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, ei
  • the radical A can also be a heterocyclic group containing at least one atom selected from the group of oxygen, nitrogen and sulphur and is for example pyridyl, pyrrolyl, pyrrolidinyl, piperidinyl, indolyl, imidazolyl, furyl, dioxolanyl, oxiranyl, thiiranyl, thiopyranyl, oxazolyl and thiazolyl.
  • substitution could consist of free functional groups such as hydroxyl, carbonyl, carboxyl, mercapto or amino or these groups could be present in protected form.
  • carboxyl groups are usually protected in esterified form and contain as esterifying groups especially lower alkyl groups, which could be branched in the 1-position or suitably substituted in the 1- or 2-position.
  • Preferred carboxyl groups protected in esterified form are inter alia methoxycarbonyl, butoxycarbonyl, tert. alkoxycarbonyl, for example tert.
  • Further preferred protected carboxyl groups in esterified form are silyloxycarbonyl groups, especially organic silyloxycarbonyl groups.
  • the silicon atom contains as substituent preferably lower alkyl, especially methyl, also alkoxy, especially methoxy and/or halogen, for example chlorine.
  • Suitable silyl-protecting groups are for example trimethylsilyl and dimethyl-tert.-butylsilyl.
  • a protected amino group may be, for example, in the form of an acylaminogroup or in the form of arylalkylamino group or azido group or sulphonated amino group.
  • acyl is for example the acyl radical of an organic carboxylic acid having for example up to 18 carbon atoms, especially of an alkanecarboxylic acid that is preferably substituted for example by halogen or aryl or of a carbonic acid semiester.
  • Such acyl groups are for example lower alkanoyl such as formyl or acetyl; halo-lower alkanoyl such as 2-chloro-and 2-bromoacetyl or lower alkoxycarbonyl straight or branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, for example tert. butyl carbonyl; arylmethoxycarbonyl having one or two aryl radicals that are unsubstituted or, in the case of phenyl, may be substituted for example by lower alkyl, especially tert.
  • lower alkanoyl such as formyl or acetyl
  • halo-lower alkanoyl such as 2-chloro-and 2-bromoacetyl or lower alkoxycarbonyl straight or branched in the 1-position of the lower alkyl radical or suitably substituted in the 1- or 2-position, for example tert. butyl carbonyl
  • lower alkyl, lower alkoxy, hydroxy, halogen and/or nitro such as unsubstituted or substituted aryloxycarbonyl, for example benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl, for example benzhydroxycarbonyl or di-(4-methoxyphenyl)-methoxycarbonyl; aroylmethoxycarbonyl for example phenacyloxycarbonyl in which the aroyl group is benzoyl that is unsubstituted or substituted for example by halogen; halo-lower alkoxycarbonyl, for example 2-bromo- or 2-iodoethoxycarbonyl; or 2-(trisubstituted silyl)-ethoxycarbonyl such as for example 2-trimethylsilylethoxycarbonyl or 2-triphenylsilylethoxycarbonyl.
  • aryloxycarbonyl for example benzyloxycarbonyl
  • An arylalkylamino group is a mono-, di- or especially a triarylalkylamino group in which the aryl radicals are especially unsubstituted or substituted phenyl radicals.
  • Such groups are for example benzylamino, diphenylmethylamino or tritylamino.
  • Amino s may also contain organic silyl groups as protecting groups.
  • Suitable silylprotecting groups are especially tri-lower alkylsilyl, such as trimethylsilyl and dimethyl-tert.-butylsilyl.
  • Preferred aminoprotecing groups are acyl radicals of carbonic acid semiesters especially tert.-butoxycarbonyl or aryloxycarbonyl that is unsubstituted or substituted for example benzyloxycarbonyl or 4-nitrobenzyloxycarbonyl or diphenylmethoxycarbonyl or 2.2.2-trichloroethoxycarbonyl.
  • sulphonated amino groups such as lower alkyl sulphonamides especially N-methyl sulphonamide and N-butylsulphonamide.
  • Hydroxy- and mercapto-protecting groups are for example acyl radicals such as lower alkanoyl that is unsubstituted or substituted, for example by halogen, such as 2.2-dichloroacetyl or especially the acyl radicals of carbonic acid semiesters mentioned in connection with the amino-protecting groups and also etherifying groups such as tert.-butyl or 2-oxa- or 2-thia-aliphatic hydrocarbon radicals, for example 1-methoxyethyl, 1-methyl-thiomethyl or 2-oxa- or 2-thia-cycloaliphatic hydrocarbon radicals, for example 2-tetrahydrofuryl or 2-tetrahydropyranyl or corresponding thia analogues and unsubstituted or substituted benzyl, diphenylmethyl there coming into consideration as substituents of the phenyl radicals, for example halogen, lower alkoxy and/or nitro.
  • halogen such as 2.2-dichlor
  • Suitable silyl protecting groups are especially lower alkylsilyl such as trimethylsilyl or dimethyl-tert.-butyl-silyl.
  • Two free functional groups may also be substituted by a common protecting group.
  • hydroxy groups may be substituted by a methylene radical that is unsubstituted or preferably substituted for example by lower alkyl, such as methyl or aryl, such as phenyl or such as methylene, isopropylidene, propylidene or benzylidene.
  • substitutions on the radical A could also consist of a halogen especially fluorine, chlorine and iodine and further by a cyano group.
  • the radical A could also be substituted with phosphorus containing radicals, such as phosphine, phosphinyl and phosphonyl and with nitrogen containing radicals such as nitro or azido.
  • the radical F can further be substituted with sulphurcontaining groups such as sulphinyl or sulphonyl and siliconcontaining groups such as silyl, silyloxy or silylthio.
  • R1, R2 and R3 can independently be etherified hydroxyl with the substitutent B.
  • B can be A as defined previously, but preferably B is a straight or branched alkyl, especially a lower alkyl such as methyl, ethyl or butyl or a higher alkyl such as octyl, decyl, dodecyl or eicosyl or an alkenyl especially vinyl, allyl or butenyl.
  • B can also be a cycloalkyl, especially cyclopropyl or cyclohexyl or a cycloalkenyl, especially cyclopentenyl or cyclooctadienyl.
  • B is an aryl, especially phenyl, biphenyl and naphtyl.
  • B radical is identical with the A radical it can be in unsubstituted or substituted form.
  • the substitution could consist of free functional groups, such as hydroxyl, carbonyl, carboxyl, mercapto or amino or these groups could be present in protected form as described above.
  • the substitution could also consist of halogen and phosphorus- and nitrogencontaining radicals.
  • the substitution consists of hydroxy or repeated fragments of hydroxyl groups etherified with carbon radicals such as polyethyleneglycol and polypropyleneglycol.
  • Other preferred substitution groups consist of a halogen, especially fluorine or chlorine or amino or protected aminogroups with carbon radicals especially alkoxycarbonyl such as methoxycarbonyl, butoxycarbonyl or aminocarbonyl or sulphur radicals such as methylsulphonyl or butylsulphonyl.
  • substitution is mercapto or phosphine.
  • B can also be an etherified hydroxyl with a carbon radical which is a glycosyl residue.
  • the glycosyl residue is derived for example from a monosaccharide such as erythrose, ribose, arabinose, allose, altrose, glucose, mannose, threose, xylose, lyxose, gulose, idose, galactose, talose, fructose or from a polysaccharide such as maltose,lactose, cellobiose or sucrose or nonhydrolyzed or partially hydrolyzed cellulose, amylose or amylopectin.
  • a monosaccharide such as erythrose, ribose, arabinose, allose, altrose, glucose, mannose, threose, xylose, lyxose, gulose, idose, galactose, talose, fructose or from
  • glycosyl residue is derived from glucose, fructose, mannose or lactose.
  • glycosyl residue could also be substituted with for example carboxyl, amino- or phosphonyl groups such as glucoseamine or galactoseamine or glucosephosphate or glucopyranosyl phosphate or sialic acid.
  • B can also be an etherified hydroxyl with a carbon radical which is a glycopeptide.
  • This radical is derived for example from one or more sugar residues which are attached primarily to serine, threonine or aspargine side chains of the peptide, where the peptide is formed by different combinations of amino acids up to a molecular weight of 10.000.
  • Prefered radicals are those which include glucoseamine or galactoseamine attached to especially di- and tripeptides.
  • B can also be an etherified hydroxyl with a carbon radical which is a glycoprotein.
  • This radical is derived for example from one or more sugar residues which are attached primarily to serine, threonine or aspargine side chains of the proteins, especially alkaline phosphatase, acetylcholinesterase, 5-nucleotidase, Thy-1, Th B and heparan sulphate proteoglycan.
  • Preferred radicals are those which include glucoseamine and galactoseamine attached to the protein.
  • Especially preferred radicals are lectins such as concanavalin A, wheat germ agglutinin, peanutagglutinin and seromucoid and orosomucoid.
  • B can also be an etherified hydroxyl with a carbon radical which is glycolipid.
  • This radical is derived for example from one or more sugar residues which are attached to a lipid.
  • Preferred radicals are those which include glucose or galactose. Further preferred radicals are cerebroside and ganglioside.
  • B can also be a halogen, especially fluorine and chlorine or a functional group such as carboxyl, phosphonyl or sulfonyl.
  • R1, R2 and R3 can independently be esterified hydroxyl with the substituent D.
  • D can be A as defined previously, but preferably the radical is derived from an organic carboxylic acid, especially an aliphatic, but also a cycloaliphatic, cycloaliphatic-aliphatic, aromatic or araliphatic carboxylic acid.
  • Aliphatic carboxylic acids are inter alia alkane carboxylic acids that are unsubstituted or substituted for example by hydroxy or etherified or esterified hydroxy such as lower alkoxy or lower alkanoyloxy, by unsubstituted or substituted amino, such as lower alkylamino, di-lower alkylamino or by acylamino for example alkanoylamino and corresponding alkene- or alkyne carboxylic acids that may have one or more double or triple bonds.
  • the radical is unsubstituted or hydroxysubstituted lower alkanecarboxylic acid such as acetic acid, butyric acid, caproic acid or 2-hydroxybutyric acid or unsubstituted or hydroxysubstituted higher alkanecarboxylic acid such as lauric acid or stearic acid.
  • the radical is also a lower alkene- and lower alkyne-carboxylic acid such as acrylic acid or crotonic acid or higher alkene- and higher alkyne-carboxylic acid such as oleic acid and arachidonic acid.
  • cycloaliphatic-aliphatic radicals the cycloaliphatic moiety and the aliphatic moiety have the meanings described above and are especially monocyclic or polycyclic cyclo-lower alkyl.
  • Aromatic and araliphatic carboxy acids are inter alia benzoic or phenyl-lower alkanecarboxylic that are unsubstituted or substituted for example by alkyl, hydroxy, lower alkoxy or halogen.
  • the radical is benzoic acid or phenolacetic acid.
  • D can also be an esterified hydroxy with a carbonradical which is a carboxy group or esterified caboxy group to form a semiester or a diester.
  • Preferred carboxygroups are lower alkane carboxyl such as acetoxy and butyryloxy.
  • D can also be an esterified hydroxyl with a radical containing nitrogen such as amino or substituted amino.
  • the radical is lower alkylamino for example methylamino, ethylamino and isopropylamino.
  • R1, R2 and R3 can independently be esterified hydroxyl with the substituent E.
  • E can be an amino acid, for example lysine, histidine, asparagine, arginine, aspartic acid, threonine, serine, glutamic acid, proline, glycine, alanine, cystine, valine, methionine, isoleucine, leucine, tyrosine, phenylalanine or tryptophan.
  • amino acid is alanine, serine, glycine, threonine, methionine, asparagine and histidine.
  • E can also be a peptide consisting of the above mentioned amino acids up to a molecular weight of 10.000.
  • Preferred radicals are dipeptides such as alanyl-alanyl, prolyl-methionyl, glycyl-glycyl or threonyl-histidyl.
  • E can also be a protein such as albumin, antitrypsin, macroglobulin, haptoglobin, caeruloplasmin, transferrin, ⁇ - or ⁇ -lipoprotein, ⁇ - or ⁇ -globulin or fibrinogen.
  • a protein such as albumin, antitrypsin, macroglobulin, haptoglobin, caeruloplasmin, transferrin, ⁇ - or ⁇ -lipoprotein, ⁇ - or ⁇ -globulin or fibrinogen.
  • R1, R2, R3, R4, R5, R6 can independently be the substituent F.
  • F can be a free functional group such as hydroxy, carbonyl, carboxyl, mercapto or amino or these could be protected with other groups as described for the radical A.
  • F can also be a halogen such as fluorine, chlorine, bromine and iodine and further a cyano or an isocyanato group.
  • F can also consist of phosphorus containing radicals such as phosphine, phosphinyl and phosphonyl or phosphorothioate and with nitrogen containing radicals such as nitro and azido.
  • F can further consist of sulphurcontaining radicals such as xanthate, sulfinyl or sulfonyl or siliconcontaining radicals such as silyl, silyloxy or silylthio.
  • F can also be a heterocyclic group containing at least one atom selected from the group of oxygen, nitrogen or sulphur.
  • F can further also be a carbamyl or substituted carbamyl.
  • R1, R2 or R3 are F the preferred radical is hydroxy, mercapto or halogen, especially fluorine and chlorine.
  • Further preferred radicals are those where F is phosphino or amino or substituted amino.
  • the substitution for the aminogroup is preferably a lower alkyl carbonyl radical such as methyl- or butylcarbonyl or sulphinyl or alkyl sulphinyl such as methyl­sulphinyl or butylsulphinyl or an aminocarbonyl such as N-methylaminocarbonyl.
  • R4, R5 or R6 are F the preferred radical is carboxy, carbamyl or substituted carbamyl, sulphonyl or substituted sulphonyl or phosphinyl or phosphonyl or substituted phosphinyl or phosphonyl.
  • F can also preferably be a heterocyclic group especially isoxazolyl, imidazolyl or thiazolyl.
  • Y is oxygen and especially preferred is when Y is oxygen and when R4, R5 and R6 all have the above formula, i.e.
  • R7 and R8 can independently be hydrogen or B as defined previously.
  • the radical is alkyl or aryl especially lower alkyl such as methyl, ethyl or butyl or higher alkyl such as octyl or dodecyl or aryl such as phenyl.
  • B is substituted alkyl such as dihydroxy propyl or esterified dihydroxypropyl.
  • R7 is hydrogen and R8 is lower alkyl especially methyl, ethyl or butyl.
  • R7 and R8 can also be another phosphoruscontaining group with the formula where R9 is hydrogen, hydroxyl or B as defined previously.
  • R9 is B the radical is alkyl or aryl especially lower alkyl such as methyl, ethyl or butyl or higher alkyl such as octyl or dodecyl or aryl such as phenyl.
  • R9 can also be an etherified hydroxyl with a radical B and preferably in this form B is alkyl or aryl as described above.
  • R4, R5, R6 are a mono- or polyphosphate or alkylated or arylated mono- or polyphosphates.
  • R7 and/or R8 can also be a radical of myo-inositol or a radical of a configuration isomer thereof or a further phosphorylated radical of a configuration isomer of myo-inositol.
  • R4, R5, R6 could independently be a phosphorus containing radical with the formula: with R7 and R9 as defined previously.
  • R7 is hydrogen and R9 is amino or substituted amino such as alkylamino, especially methyl- or butylamino.
  • One embodiment of this invention relates to a compound of Formula (I), wherin R1, R2, R3 independently are
  • R1 or preferably R1 and R2 are hydroxyl while R2 and R3 or preferably only R3 are selected from the group of hydrogen, oxygen, F or A as defined previously.
  • R2 and R3 or only R3 are chlorine, bromine or iodine or most preferably fluorine.
  • R2 and R3 or only R3 are amino or substituted amino especially where the substitution on the aminogroup is a lower alkyl carbonyl radical such as methyl- or butylcarbonyl or sulphinyl or alkylsulphinyl radical such as methyl- or butylsulphinyl or an aminocarbonyl or a substituted aminocarbonyl such as N-methylaminocarbonyl.
  • R2 and R3 or only R3 are unsubstituted or substituted mercapto, the substitution being preferably lower alkyl such as methyl- or butylmercapto.
  • R2 and R3 or only R3 are a phosphino, a xanthate or an isocyanatogroup.
  • R2 and R3 or only R3 are alkyl or aryl in unsubstituted or substituted form, especially lower alkyl such as ethyl and butyl and substituted ethyl and butyl with hydroxyl, mercapto, amino or phosphino or aryl such as phenyl.
  • R2 and R3 or only R3 are hydrogen or oxygen.
  • R1, R2, R3 are the same selected from
  • R4 and R5 are while R6 is F.
  • R4, R5 and R6 are where Y is oxygen and R7, R8 are hydrogen or alkyl such as methyl, ethyl or butyl or aryl such as phenyl.
  • R1, R2, R3 are the same and preferably hydrogen, oxygen, chlorine, bromine and iodine or most preferably fluorine.
  • R1, R2 and R3 are amino or substituted amino especially where the substitution on the amino group is a lower alkylcarbonyl radical such as methyl- or butylcarbonyl or sulphinyl or alkylsulphinyl radical such as methyl- and butylsulphinyl or an aminocarbonyl or substituted aminocarbonyl such as N-methylaminocarbonyl.
  • R1, R2 and R3 are unsubstituted or substituted mercapto, the substitution being preferably lower alkyl such as methyl- or butylmercapto.
  • R1, R2 and R3 are phosphino, xanthate or isocyanatogroups.
  • R1, R2 and R3 are alkyl or aryl in unsubstituted form, especially lower alkyl such as ethyl and butyl or substituted ethyl and butyl with hydroxyl, mercapto, amino or phosphino or aryl such as phenyl.
  • R1, R2 and R3 independently are covalently bound to C3, C4 and C5 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C6 in myo-inositol such as follows:
  • R1, R2 and R3 are independently bound to C4, C5 and C6 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C3 in myo-inositol such as follows: or where R1, R2 and R3 are independently covalently bound to C2, C5 and C6 and R4, R5 and R6 independently are covalently bound to C1, C3 and C4 in myo-inositol such as follows:
  • R1 and R2 are hydroxyl and R3 are as described above and R4, R5 and R6 are where Y is oxygen and R7 and R8 are hydrogen:
  • R3 is especially selected from the group of hydrogen, oxygen, fluorine, chlorine, bromine and iodine and most preferably fluorine or selected from the group of amino or substituted amino especially where the substitution is a lower alkyl carbonyl radical such as methyl- or butylcarbonyl or sulphinyl or alkylsulphinyl radical such as methyl- or butylsulphinyl or an aminocarbonyl or a substituted aminocarbonyl such as N-methylaminocarbonyl or selected from the group of unsubstituted or substituted mercapto, the substitution being preferably lower alkyl such as methyl- ­or butylmercapto or phosphino; or selected from the group of alkyl or aryl in unsubstituted form, especially lower alkyl such as ethyl and butyl or substituted ethyl or butyl with hydroxyl
  • R1 and R2 are hydroxyl and R3 are as described above and R4, R5 R6 are where Y is oxygen and where R7, R8 preferably are lower alkyl such as methyl and butyl:
  • R1, R2 and R3 are the same and as described above and R4, R5, R6 are where Y is oxygen and R7, R8 are hydrogen:
  • R1, R2, R3 are especially selected from the group of hydrogen, oxygen, fluorine, chlorine, bromine and iodine and most preferably fluorine; or selected from the group of amino or substituted amino, especially where the substitution is a lower alkylcarbonyl radical such as methyl- or butylcarbonyl radicals or sulphinyl or alkylsulphinyl radical such as methyl- or butylsulphinyl or an aminocarbonyl or a substituted aminocarbonyl such as N-methyl aminocarbonyl or selected from the group of unsubstituted or substituted mercapto, the substitution being preferably lower alkyl such as methyl- or butyl mercapto or phosphino; or selected from the group of alkyl or aryl in unsubstituted from, especially lower alkyl such as ethyl and butyl or substituted ethyl or butyl with hydroxyl, mercapto, amino or phosphino or ary
  • R1, R2 and R3 are as described above and R4, R5 and R6 are where Y is oxygen and where R7 and R8 preferably is lower alkyl such as methyl and butyl:
  • One embodiment of this invention relates to a compound of Formula (I) wherein R1, R2 and R3 independently are:
  • R1 or preferably R1 and R2 are hydroxyl, while R2 and R3 or preferably only R3 are etherified hydroxyl with the substituent B, where B is A as defined previously or a glycosyl residue, a glycopeptide, a glycoprotein, a glycolipid or selected from the group of halogen, carboxy, phosphonyl or sulphonyl.
  • B is preferably a straight or branched alkyl, especially a lower alkyl such as methyl, ethyl or butyl or a higher alkyl such as octyl, dodecyl and eicosyl or an alkenyl, especially vinyl, alkyl or butenyl.
  • B can also be a cycloalkyl, especially cyclopropyl or cyclohexyl or aryl, especially phenyl, biphenyl or naphtyl.
  • the above mentioned radicals can be unsubstituted or substituted especially with hydroxyl, mercapto, carboxyl, amino or phosphino.
  • By preference B can also be a glycosyl residue especially glucose, mannose, maltose, glucoseamine or glucosephosphate; or a glycopeptide especially a glycopeptide including glucoseamine or galactoseamine attached to di- and tripeptides such as alanyl-alanyl, prolyl-methionyl or glycyl-glycyl; or a glycoprotein, especially a glycoprotein including glucoseamine or galactoseamine attached to a protein such as concanavalin A, wheat germ agglutinin and peanutagglutinin; or a glycolipid especially a glycolipid including glucose or galactose such as cerebroside and ganglioside.
  • a glycosyl residue especially glucose, mannose, maltose, glucoseamine or glucosephosphate
  • a glycopeptide especially a glycopeptide including glucoseamine or galactoseamine attached to di- and tripeptides such as alanyl-alanyl, prolyl-methionyl or
  • B can preferably also be halogen, especially fluorine or chlorine or carboxyl, phosphonyl or sulphinyl.
  • substitution OB are repeated fragments of hydroxyl groups etherified with carbon radicals such as polyethyleneglycol or polypropyleneglycol.
  • R1, R2 and R3 are the same i.e. etherified hydroxyls with the carbon radical B as previously defined.
  • X is a radical of a configuration isomer of inositol and preferably a radical of myo-inositol.
  • R4, R5 and R6 are where Y, R7, R8 and F are as defined previously.
  • R4 and R5 are while R6 is F.
  • R4, R5 and R6 are where Y is oxygen and R7 and R8 are hydrogen or alkyl such as methyl, ethyl or butyl or aryl such as phenyl.
  • R1, R2 and R3 are the same, that is etherified hydroxyl with the substituent B, which preferably is a straight or branched alkyl, especially a lower alkyl such as methyl, ethyl or butyl or a higher alkyl such as octyl, dodecyl or eicosyl or an alkenyl, especially vinyl, alkyl or butenyl.
  • B can also be a cycloalkyl, especially cyclopropyl or cyclohexyl or aryl, especially phenyl, biphenyl or naphtyl.
  • the above mentioned radicals can be unsubstituted or substituted, especially with hydroxyl, mercapto, carboxyl, amino or phosphino.
  • B can also be a glycosyl residue, especially glucose, mannose, maltose, glucoseamine or glucosephosphate; or a glycopeptide, especially a glycopeptide including glucoseamine or galactoseamine attached to di- and tripeptides such as alanyl-alanyl, prolyl-methionyl or glycyl-glycyl; or a glycoprotein, especially a glycoprotein including glucoseamine or galactoseamine attached to a protein such as concanavalin A, wheat germ agglutinin and peanutagglutinin; or a glycolipid especially a glycolipid including glucose or galactose such as cerebroside and ganglioside.
  • a glycosyl residue especially glucose, mannose, maltose, glucoseamine or glucosephosphate
  • a glycopeptide especially a glycopeptide including glucoseamine or galactoseamine attached to di- and tripeptides such as alanyl-alanyl, prolyl-methionyl or
  • B can preferably also be a halogen, especially fluorine or chlorine or carboxyl, phosphonyl or sulphinyl.
  • substitution OB are repeated fragments of hydroxyl groups etherified with carbon radicals such as polyethyleneglycol or polypropyleneglycol.
  • R1, R2 and R3 independently are covalently bound to C3, C4 and C5 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C6 in myo-inositol such as follows:
  • R1, R2 and R3 independently are covalently bound to C4, C5 and C6 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C3 in myo-inositol such as follows: or where R1, R2 and R3 independently are covalently bound to C2, C5 and C6 and R4, R5 and R6 independently are covalently bound to C1, C3 and C4 in myo-inositol such as follows:
  • R1 and R2 are hydroxyl and R3 are as described above and R4, R5 and R6 are where Y is oxygen and R7 and R8 are hydrogen:
  • B is especially selected from the group of straight or branched alkyl such as methyl, butyl, dodecyl or eicosyl or alkenyl such as allyl or butenyl or cycloalkyl such as cyclopropyl or cyclohexyl or aryl such as phenyl unsubstituted or substituted especially with hydroxyl, mercapto, carboxyl, amino or phosphino; or selected from the group of a glycosyl residue especially glucose, mannose, glucoseamine or glucosephosphate or a glycopeptide especially including a glucoseamine or galactoseamine attached to a di- or tripeptide, or a glycoprotein especially including a glucoseamine or galactoseamine attached to the protein or a glycolipid including glucose or galactose; or selected from the group of halogen, especially fluorine or chlorine, or carboxy, phosphonyl or sulphinyl; or selected from the group consisting of repeated fragments of
  • R1 and R2 are hydroxyl and R3 are described as above and R4, R5 and R6 are where Y is oxygen and where R7 and R8 preferably are lower alkyl such as methyl and butyl:
  • R1, R2 and R3 are the same and as described above and R4, R5 and R6 are where Y is oxygen and R7 and R8 are hydrogen:
  • B is especially selected from the group of straight or branched alkyl, such as methyl-, butyl, dodecyl or eicosyl or alkenyl such as allyl or butenyl or cycloalkyl such as cyclopropyl or cyclohexyl or aryl such as phenyl, unsubstituted or substituted especially with hydroxyl, mercapto, carboxyl, amino or phosphino; or selected from the group of a glycosyl residue especially glucose, mannose, glucoseamine or glucosephosphate or a glycopeptide especially including a glucoseamine or galactoseamine attached to a di- or tripeptide, or a glycoprotein especially including a glucoseamine or galactoseamine attached to the protein or a glycolipid including glucose or galactose, or selected from the group of halogen, especially fluorine or chlorine or carboxy, phosphonyl or sulphinyl; or selected from the group consisting of repeated fragments
  • R1, R2 and R3 are the same and as described above and R4, R5 and R6 are where Y is oxygen and where R7 and R8 preferably are lower alkyl such as methyl and butyl:
  • One embodiment of this invention relates to a compound of Formula (I) wherein R1, R2 and R3 independently are
  • R1 or preferably R1 and R2 are hydroxyl while R2 and R3 or preferably only R3 are selected from the group of esterified hydroxyl with the substituents D or E, where D is A as defined previously, carboxy or esterified carboxy, amino or substituted amino and where E is an amino acid, peptide or a protein.
  • D is preferably a radical derived from an organic carboxylic acid, especially an unsubstituted or substituted aliphatic acid such as acetic acid, butyric acid, caproic acid, lauric acid or 2-hydroxy butyric acid or an alkenic acid, such as acrylic acid or crotonic acid or an aromatic acid such as benzoic acid or phenylacetic acid.
  • D is also an esterified hydroxyl with a carbon radical which is a carboxy group or esterified carboxy group, especially acetoxy and butyryloxygroups or a radical containing nitrogen such as amino or substituted amino, especially methyl-, ethyl- and isopropylamino.
  • E is an amino acid, especially asparginine, histidine, methionine and serine or a peptide consisting of amino acids up to a molecular weight of 10.000, especially dipeptides such as alanyl-alanyl, prolyl-methionyl and glycyl-glycyl or a protein, especially albumin, transferrin, ⁇ - and ⁇ -lipoprotein, ⁇ - and ⁇ -globulin and fibrinogen.
  • dipeptides such as alanyl-alanyl, prolyl-methionyl and glycyl-glycyl or a protein, especially albumin, transferrin, ⁇ - and ⁇ -lipoprotein, ⁇ - and ⁇ -globulin and fibrinogen.
  • R1, R2 and R3 are the same selected from:
  • R4 and R5 are while R6 is F.
  • R4, R5 and R6 are where Y is oxygen and R7 and R8 are hydrogen or alkyl, such as methyl, ethyl or butyl or aryl such as phenyl.
  • R1, R2 and R3 are the same, that is esterified hydroxyl with the substituents D or E, where D preferably is a radical derived from an organic carboxylic acid, especially an unsubstituted or substituted aliphatic acid, such as acetic acid, butyric acid, caproic acid, lauric acid and 2-hydroxy butyric acid or an alkenic acid, such as acrylic acid or crotonic acid or an aromatic acid, such as benzoic acid or phenylacetic acid.
  • D preferably is a radical derived from an organic carboxylic acid, especially an unsubstituted or substituted aliphatic acid, such as acetic acid, butyric acid, caproic acid, lauric acid and 2-hydroxy butyric acid or an alkenic acid, such as acrylic acid or crotonic acid or an aromatic acid, such as benzoic acid or phenylacetic acid.
  • D is also an esterified hydroxyl with a carbon radical which is a carboxy group or esterified carboxy group, especially acetoxy and butyryloxy groups or a radical containing nitrogen, such as amino or substituted amino, especially methyl-, ethyl- and isopropylamino.
  • E is an amino acid, especially asparagine, histidine, methionine and serine or a peptide consisting of amino acids up to a molecular weight of 10.000, especially dipeptides such as alanyl-alanyl, prolyl-methionyl and glycyl-glycyl or a protein, especially albumin, transferrin, ⁇ - ­and ⁇ -lipoprotein, ⁇ - and ⁇ -globulin and fibrinogen.
  • dipeptides such as alanyl-alanyl, prolyl-methionyl and glycyl-glycyl or a protein, especially albumin, transferrin, ⁇ - ­and ⁇ -lipoprotein, ⁇ - and ⁇ -globulin and fibrinogen.
  • R1, R2 and R3 independently are covalently bound to C3, C4 and C5 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C6 in myo-inositol such as follows:
  • R1, R2 and R3 independently are covalently bound to C4, C5 and C6 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C3 in myo-inositol such as follows: or where R1, R2 and R3 independently are covalently bound to C2, C5 and C6 and R4, R5 and R6 independently are covalently bound to C1, C3 and C4 in myo-inositol such as follows:
  • R1 and R2 are hydroxyl and R3 are as described above and R4, R5 and R6 are where Y is oxygen and R7 and R8 are hydrogen:
  • D is especially selected from the group of radicals derived from organic carboxylic acids such as acetic acid, butyric acid, lauric acid, 2-hydroxy butyric acid, acrylic acid and benzoic acid; or selected from the group of carboxy or esterified carboxy such as acetoxy and butyryloxy; or selected from the group of amino or substituted amino such as methyl- or isopropylamino.
  • E is especially selected from the group of amino acids, such as asparagine, histidine, methionine or serine or selected from the group of peptides such as alanyl-alanyl, or prolyl-methionyl or selected from the group of proteins, such as albumin, transferrin and ⁇ - and ⁇ -lipoprotein.
  • amino acids such as asparagine, histidine, methionine or serine
  • peptides such as alanyl-alanyl, or prolyl-methionyl
  • proteins such as albumin, transferrin and ⁇ - and ⁇ -lipoprotein.
  • R1 and R2 are hydroxyl and R3 are as described above and R4, R5 and R6 are where Y is oxygen and where R7 and R8 preferably are lower alkyl such as methyl and butyl:
  • R1, R2 and R3 are the same and as described above and R4, R5 and R6 are where Y is oxygen and R7 and R8 are hydrogen:
  • R1, R2 and R3 are the same and are O - - D, where D is especially selected from the group of radicals derived from organic carboxylic acids such as acetic acid, butyric acid, lauric acid, 2-hydroxybutyric acid, acrylic acid and benzoic acid; or selected from the group of carboxy or esterified carboxy, such as acetoxy and butyryloxy; or selected from the group of amino or substituted amino, such as methyl- or isopropylamino; or E where E is especially selected from the group of amino acids, such as asparagine, histidine, methionine and serine; or selected from the group of peptides such as alanyl-alanyl or prolyl-methionyl or selected from the group of proteins such as albumin, transferrin and ⁇ - and ⁇ -lipoproteins.
  • D is especially selected from the group of radicals derived from organic carboxylic acids such as acetic acid, butyric acid, lauric acid, 2-hydroxybuty
  • R1, R2 and R3 are the same and as described above and R4, R5 and R6 are where Y is oxygen and where R7 and R8 preferably are lower alkyl such as methyl and butyl:
  • One embodiment of this invention relates to a compound of Formula (I), wherein R1, R2 and R3 independently are as defined previously and where X is a radical of myo-inositol or a radical of a configuration isomer thereof and where R4, R5 and R6 are where Y, R7 and R8 are as defined previously.
  • Y is preferably oxygen and R7 and R8 are independently hydrogen or the radical B, especially unsubstituted alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl or substituted alkyl such as dihydroxypropyl or esterified dihydroxypropyl; or E, especially an aminc acid such as methionine or glycine.
  • B especially unsubstituted alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl or substituted alkyl such as dihydroxypropyl or esterified dihydroxypropyl
  • E especially an aminc acid such as methionine or glycine.
  • R7 and R8 independently are another phosphorus containing group with the formula: wherein R9 is hydrogen, hydroxyl or B, especially selected from the group of alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl or OB, especially methoxy, ethoxy, butoxy or phenoxy, or E, especially methionine or glycine, or X i.e. another configuration isomer of inositol or a phosphorylated configuration isomer of inositol or amino or substituted amino such as methyl- or butylamino.
  • R9 is hydrogen, hydroxyl or B, especially selected from the group of alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl or OB, especially methoxy, ethoxy, butoxy or phenoxy, or E, especially methi
  • R1, R2 and R3 are as defined previously, X is a radical of myo-inositol or a radical of a configuration isomer thereof and R4, R5 and R6 are where R7 and R9 are as defined previously.
  • R7 is preferably hydrogen or the radical B, especially unsubstituted alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl or substituted alkyl such as dihydroxypropyl or esterified dihydroxypropyl or E, especially an amino acid such as methionine or glycine.
  • R9 is preferably hydrogen, hydroxyl or B, especially selected from the group of alkyl such as methyl, ethyl, butyl, octyl, dodecyl or aryl such as phenyl or OB, especially methoxy, ethoxy, butoxy or phenoxy or E, especially methionine or glycine or X, i.e. another configuration isomer of inositol or a phosphorylated configuration isomer or amino or substituted amino such as methyl- or butylamino.
  • R1, R2 and R3 are as defined previously, X is a radical of myo-inositol or a radical of a configuration isomer thereof and R4, R5 and R6 are F, where F is as defined previously.
  • F is preferably carboxyl or unsubstituted or substituted carbamyl, the substitution being preferably N-methyl-, N-propyl- or N-cyanocarbamyl or sulphonyl or substituted sulphonyl, especially aminosulphinyl or N-methyl- or N-butylaminosulphinyl.
  • Other preferred forms of F are where F is phosphonyl or substituted phosphonyl such as aminophosphonyl or phosphorothioate.
  • F can also be a heterocyclic group, especially isoxazolyl, imidazolyl or thiazolyl.
  • R1, R2 and R3 independently are as defined previously and X is a radical of a configuration isomer of inositol and preferably a radical of myo-inositol.
  • R4, R5 and R6 are and R6 is F, where Y, R7, R8, R9 and F is as defined previously.
  • Y is preferably oxygen and R7 and R8 are independently hydrogen or the radical B, especially unsubstituted alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl or substituted alkyl such as dihydroxypropyl or esterified dihydroxypropyl; or E, especially an amino acid such as methionine or glycine.
  • B especially unsubstituted alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl or substituted alkyl such as dihydroxypropyl or esterified dihydroxypropyl
  • E especially an amino acid such as methionine or glycine.
  • R9 is preferably hydrogen, hydroxyl or the radical B, especially selected from the group of alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl; or OB, especially methoxy, ethoxy, butoxy or phenoxy; or E, especially methionine or glycine or X i.e. another configuration isomer of inositol, preferably myo-inositol or a phosphorylated isomer of myo-inositol; or amino or substituted amino such as methyl- or butylamino.
  • B especially selected from the group of alkyl such as methyl, ethyl, butyl, octyl or dodecyl or aryl such as phenyl
  • OB especially methoxy, ethoxy, butoxy or phenoxy
  • E especially methionine or glycine or X i.e
  • F is preferably carboxyl; or unsubstituted or substituted carbamyl, especially N-methyl-, N-propyl- or N-cyanocarbamyl; or sulphonyl or substituted sulphonyl, especially aminosulphonyl or N-methyl- or N-butyl aminosulphonyl; or phosphonyl or substituted phosphonyl, especially aminophosphinyl; or a heterocyclic group, especially isoxazolyl, imidazolyl or thiazolyl.
  • R1, R2 and R3 independently are covalently bound to C3, C4 and C5 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C6 in myo-inositol such as follows:
  • R1, R2 and R3 independently are covalently bound to C4, C5 and C6 and where R4, R5 and R6 independently are covalently bound to C1, C2 and C3 in myo-inositol such as follows: or where R1, R2 and R3 independently are covalently bound to C2, C5 and C6 and where R4, R5 and R6 independently are covalently bound to C1, C3 and C4 in myo-inositol such as follows:
  • R1, R2 and R3 are hydroxyl and R4, R5 and R6 are
  • Y is oxygen and R7 and/or R8 are hydrogen; or methyl, ethyl, butyl, octyl, dodecyl, phenyl, dihydroxypropyl or esterified dihydroxypropyl, especially with C14 to C20 alkylcarbonyl groups; or glycine, methionine or histidine.
  • R1, R2 and R3 are hydroxyl and R4, R5 and R6 are
  • R7 is hydrogen; or methyl, ethyl, butyl, octyl, dodecyl, phenyl, dihydroxypropyl or esterified dihydroxypropyl with C14 to C20 -alkylcarbonyl groups; or glycine, methionine or histidine and R9 is preferably hydrogen or hydroxyl; or methyl, ethyl, butyl, octyl, dodecyl or phenyl; or methoxy, ethoxy, butoxy or phenoxy; or glycine or methionine; or another configuration isomer of myo-inositol or a phosphorylated isomer of myo-inositol; or amino, methyl- or butylamino.
  • R1, R2 and R3 are hydroxyl and R4, R5 and R6 are F:
  • F is carboxyl; or carbamyl, N-methylcarbamyl, N-propylcarbamyl or N-cyanocarbamyl; or sulphonyl, aminosulphonyl, N-methyl- or N-butylaminosulphonyl; or phosphonyl or aminophosphonyl; or isoxazolyl, imidazolyl or thiazolyl.
  • R1, R2 and R3 are hydroxyl and R4 and R5 are and R6 is F.
  • F and R4 and R5 could be in changed positions independently to each other.
  • Y is oxygen and R7 and/or R8 are hydrogen or methyl, ethyl, butyl, octyl, dodecyl, phenyl, dihydroxypropyl or esterified dihydroxypropyl, especially with C14 to C20 -alkyl carbonyl groups; or glycine, methionine or histidine, and F is hydroxyl or carboxyl; or carbamyl, N-methylcarbamyl, N-propylcarbamyl or N-cyanocarbamyl; or sulphonyl, aminosulphonyl, N-methyl- or N-butylaminosulphonyl; or phosphonyl or amino­phosphonyl; or isoxazolyl, imidazolyl or thiazolyl.
  • R1, R2, R3 and R6 are hydroxyl and R4 and R5 are phosphate:
  • R1 is OB and R2 is hydroxyl or OB, R3, R4, R5 are hydroxyl and R6 are with the following formula: In this formula R2, R6 and OB could be in changed positions independently to each other.
  • Y is oxygen and R7 and/or R8 are hydrogen; or dodecyl or eicosyl; or esterified dihydroxypropyl, especially with C14 to C20 -alkylcarbonyl groups and R9 is hydrogen, hydroxyl or amino or another configuration isomer of myo-inositol or a phosphorylated isomer of myo-inositol.
  • B is a glycosyl residue, especially glucose or mannose or glucosamine or a glycoprotein.
  • the described compounds can also exist in dimeric or polymeric forms.
  • the described substituents could per se be e.g. pharma­ceutically active compounds.
  • the invention also relates to a composition comprising one or more compounds of Formula (I) as defined previously.
  • the composition usually contains 10 to 99.5 %, preferably 20 to 99.5 % of these compounds.
  • the invention relates to the above mentioned compounds as pharmaceutically active substances, their use for the manufacture of pharmaceutical preparations and to pharmaceutical preparations containing these compounds.
  • the invention also relates to the above mentioned compounds as additives for foodstuffs or stabilizers for different products.
  • the present invention particularly aims at a method of reducing the negative effect of various metal ions, e.g. cadmium, alumi­ nium, lead, mercury, nickel or chromium ions or free radicals in the body tissues.
  • Said method comprises administering to a person or an animal, i.e. mammals, an amount of inventive com­pounds to interfere with such metal ion or inhibit or reduce the formation of free radicals in the body.
  • the invention also comprises a method of preventing or allevia­ting one of the following conditions: an arthritic condition, bronchitis, a cell proliferation change, a cancer, high blood pressure, a cardiovascular disease, age diabetes, damage to the placenta, damage to the testicles, damage of different parts of the eye such as retina tissue and lens, damage to the prostate, damage to cell membranes, damage to the central nervous system, damage to the conducting system of the heart, emphysema, lung fibrosis, migraine headache, menstruation disorders, endothe­lium damage, kidney damage, thrombosis, multiple sclerosis, increased platelet aggregation, inhibition of the prostacycline production, metal intoxication, allergy caused by lead, mer­cury, nickel or chromium, inflammatory conditions, damage to the connective tissue, liver damage, brain damage, immuno­deficiency, conditions of shock, gastroenteritis, dermatitis and neurological disturbance. Said conditions are attributable to or are caused or aggravated by
  • the method comprises administering to a human or an animal an amount of chosen compound sufficient to obtain said prevention or alleviation.
  • the invention covers a method of alleviating the detrimental effect of radiation in the body, which method comprises administering to a human or an animal an amount of the inventive compound sufficient to alleviate said effect of radiation.
  • the radiation can be X-ray or nuclear radiation, but other kinds of radiation are also contemplated.
  • D-myo-inositol-1,2,6-triphosphate in acid form was freeze-dried in a vial.
  • Two hundred mg sodiumhydroxide was dissolved in 5 ml dimethylsulphoxide (DMSO) and added to the vial.
  • Five hundred ⁇ l dimethylsulphate was added and the mixture was stirred under dry nitrogen atmosphere for one hour.
  • DMSO dimethylsulphoxide
  • the mixture was sonicated for 60 hrs and then evaporated to dryness.
  • Structural determination showed the product to be D-3,4,5-tri-O-acetyloxy-myo-inositol-1,2,6-triphosphate.
  • D-myo-inositol-1,2,6-triphosphate was mixed with 600 mg sodiumhydroxide in two ml water. To this solution 550 mg sodiumchloracetate was added and the reaction mixture was heated to 70°C for 5 hrs. After cooling to room temperature the mixture was neutralized with 2.0 M hydrochloric acid and calcium chloride was added to give a precipitate, which was shown to be D-3,4,5-tri-O-carboxy-myo-inositol-1,2,6­-triphosphate.
  • D-4-oxy-myo­-inositol-1,2,6-triphosphate was dissolved in 10 ml water and hydroxylamine hydrochloride (110 mg) and an aqueous solution of sodium acetate (100 mg in 5 ml water) was added dropwise under stirring. The mixture was stirred further for 2.5 hours at room temperature.
  • D-myo-inositol-1,2,6-triphosphate was freeze-dried in a vial.
  • One ml of N,O-bis(trimethylsilyl)trifluoracetamide-chlorotrimethylsi­lane-pyridine (9:9:10;v:v:v) was added and taken to dryness under a stream of nitrogen and then dissolved in 1.0 ml of 10 % anhydrous methanol in diethyl ether at 0°C. After 15 minutes the mixture was evaporated and structural determination of the residue showed it to be D-3,4,5-tri-O-trimethylsilyl-myo-inositol--1,2,6-triphosphate.
  • Tablets of the calcium salt of triethylether of myo-inositol-­1,2,3-triphosphate were produced in the following way. 50 g calcium salt of triethylether of myo-inositol-1,2,3-triphos­phate, 132 g lactose and 6 g acacia were mixed. Purified water was then added to the mixture, whereupon the mixing was con­tinued until a suitable consistency was obtained. The mixture was sieved and dried. Then the mixture was blended with 10 g talcum and 2 g magnesium stearate. The mixture was compressed into tablets each weighing 200 mg.
  • Tablets of the calcium salt of monododecylester of D-myo-­inositol-1,2,6-triphosphate were produced in the following way. 50 g calcium salt of monodedecylester of D-myo-inositol-1,2,6-­triphosphate, 132 g lactose and 6 g acacia were mixed. Purified water was then added to the mixture, whereupon the mixing was continued until a suitable consistency was obtained. The mixture was sieved and dried. Then the mixture was blended with 10 g talcum and 2 g magnesium stearate. The mixture was compressed into tablets each weighing 200 mg.

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  • Saccharide Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP87117481A 1986-11-26 1987-11-26 Dérivés du cyclohexane, préparations les contenant et leur utilisation Expired - Lifetime EP0269105B1 (fr)

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SE8605063A SE8605063D0 (sv) 1986-11-26 1986-11-26 Derivatives of cyclohexane
SE8605063 1986-11-26

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DE (2) DE3740152A1 (fr)
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Cited By (13)

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Publication number Priority date Publication date Assignee Title
WO1989000156A1 (fr) * 1987-07-02 1989-01-12 3I Research Exploitation Limited Preparation d'isomeres de derives de myo-inositol
EP0520372A1 (fr) * 1991-06-26 1992-12-30 Hoechst Aktiengesellschaft Analogues de phosphate d'inositol comme substances à action antagoniste du calcium
WO1993001197A1 (fr) * 1991-07-03 1993-01-21 Perstorp Ab Derives d'inositol, leurs preparations et utilisations
WO1995014477A1 (fr) * 1993-11-22 1995-06-01 Perstorp Ab Emploi d'un ester d'inositoltriphosphate pour le traitement de troubles inflammatoires
WO1995014476A1 (fr) * 1993-11-22 1995-06-01 Perstorp Ab Emploi d'un ester d'inositoltriphosphate pour la preparation d'un analgesique
WO1995014475A1 (fr) * 1993-11-22 1995-06-01 Perstorp Ab Emploi d'un ester d'inositoltriphosphate pour la preparation de medicaments
WO1997023229A1 (fr) * 1995-12-21 1997-07-03 Perstorp Ab Utilisation d'un ester d'inositoltrisphosphate pour la preparation de medicaments
WO1997049408A1 (fr) * 1996-06-24 1997-12-31 Perstorp Ab Utilisation de composes modulateurs du facteur de croissance
US7479535B2 (en) 2002-02-25 2009-01-20 Guilford Pharmaceuticals, Inc. Phosphorous-containing compounds with polymeric chains, and methods of making and using the same
WO2017098047A1 (fr) * 2015-12-11 2017-06-15 ETH Zürich Dérivés d'inositol à utiliser dans la cristallisation pathologique
US10487097B2 (en) 2015-12-11 2019-11-26 Eth Zurich 4,6-di-(O-thiophosphate)-inositol-1,2,3,5-tetra-O-sulfate for C. difficile infection
US11028112B2 (en) 2015-12-11 2021-06-08 Eth Zurich Inositol derivatives for use in pathological crystallization
US11707470B2 (en) 2015-12-11 2023-07-25 Eth Zurich Inositol derivatives for use in pathological crystallization

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US5274161A (en) * 1986-11-26 1993-12-28 Perstorp Ab Derivatives of cyclohexane
SE8605063D0 (sv) * 1986-11-26 1986-11-26 Matti Siren Derivatives of cyclohexane
EP0579957A1 (fr) 1987-07-02 1994-01-26 3i RESEARCH EXPLOITATION LIMITED Préparation d'isomères de dérivés de myoinositol
US20030147937A1 (en) * 2000-04-12 2003-08-07 Thomas Schwarz Use of compatible solutes as substances having free radical scavenging properties
US20040028631A1 (en) * 2000-08-18 2004-02-12 Thomas Schwarz Cosmetic formulations
JP2004518639A (ja) * 2000-11-21 2004-06-24 イノロジック， インコーポレイテッド 塩化物分泌を増加しそして炎症を阻害するためのイノシトール誘導体
US20070129336A1 (en) * 2003-03-27 2007-06-07 Inologic, Inc. Camphanylidene and phenylalkyl inositol polyphosphate compounds, compositions, and methods of their use
AU2008219599A1 (en) * 2007-03-01 2008-09-04 Concourse Health Sciences Llc Isomers of inositol niacinate and uses thereof
JP4925461B2 (ja) * 2007-12-25 2012-04-25 株式会社錢高組 鋼管を使用した土留め構造体、その構築方法及びシールドマシンの発進到達工法
GB0920985D0 (en) * 2009-11-30 2010-01-13 Queen Mary & Westfield College Novel inositol phosphate derivatives
US9751903B2 (en) 2011-09-29 2017-09-05 Eth Zurich Pharmaceutical compounds for use in the therapy of clostridium difficile infection
EA024069B1 (ru) * 2011-09-29 2016-08-31 Этх Цюрих Фармацевтические соединения для применения в терапии инфекции clostridium difficile

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FR1604995A (en) * 1968-12-27 1972-06-26 Metal inositol hexaphosphates - from inositol hexaphosphoric acid and organo metal cpd in anhydrous medium
SE465951B (sv) * 1984-10-23 1991-11-25 Perstorp Ab Isomer av inositoltrifosfat foeretraedesvis i saltform foer anvaendning som terapeutiskt eller profylaktiskt medel samt kompositioner daerav
DE3783694T2 (de) * 1986-03-11 1993-05-19 Mitsui Toatsu Chemicals Verfahren zur herstellung von myoinositolabkoemmlingen.
SE8605063D0 (sv) * 1986-11-26 1986-11-26 Matti Siren Derivatives of cyclohexane
US4873355A (en) * 1987-05-29 1989-10-10 E. I. Du Pont De Nemours And Company Process for regioselectively preparing phosphorylated inositols and other cyclitols
JPS63198642U (fr) * 1987-06-11 1988-12-21

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BIOCHEM. BIOPHYS. RES. COMMUN., vol. 120, no. 2, 1984, pages 481

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1989000156A1 (fr) * 1987-07-02 1989-01-12 3I Research Exploitation Limited Preparation d'isomeres de derives de myo-inositol
EP0520372A1 (fr) * 1991-06-26 1992-12-30 Hoechst Aktiengesellschaft Analogues de phosphate d'inositol comme substances à action antagoniste du calcium
US5395828A (en) * 1991-06-26 1995-03-07 Hoechst Aktiengesellschaft Inositol phosphate analogues as calcium-antagonistic substances
WO1993001197A1 (fr) * 1991-07-03 1993-01-21 Perstorp Ab Derives d'inositol, leurs preparations et utilisations
US5306841A (en) * 1991-07-03 1994-04-26 Bundgaard Hans Derivatives of inositol, preparations containing them and their use
WO1995014477A1 (fr) * 1993-11-22 1995-06-01 Perstorp Ab Emploi d'un ester d'inositoltriphosphate pour le traitement de troubles inflammatoires
WO1995014476A1 (fr) * 1993-11-22 1995-06-01 Perstorp Ab Emploi d'un ester d'inositoltriphosphate pour la preparation d'un analgesique
WO1995014475A1 (fr) * 1993-11-22 1995-06-01 Perstorp Ab Emploi d'un ester d'inositoltriphosphate pour la preparation de medicaments
US5846957A (en) * 1993-11-22 1998-12-08 Perstorp Ab Use of an ester of inositoltrisphosphate for the preparing of medicaments
US5866557A (en) * 1993-11-22 1999-02-02 Perstorp Ab Use of an ester of inositoltrisphosphate for the treatment of inflammatory conditions
WO1997023229A1 (fr) * 1995-12-21 1997-07-03 Perstorp Ab Utilisation d'un ester d'inositoltrisphosphate pour la preparation de medicaments
WO1997049408A1 (fr) * 1996-06-24 1997-12-31 Perstorp Ab Utilisation de composes modulateurs du facteur de croissance
US8258255B2 (en) 2002-02-25 2012-09-04 Eisai Inc. Phosphorus-containing compounds with polymeric chains, and methods of making and using the same
US7674875B2 (en) 2002-02-25 2010-03-09 Eisai Inc. Phosphorus-containing compounds with polymeric chains, and methods of making and using the same
US7479535B2 (en) 2002-02-25 2009-01-20 Guilford Pharmaceuticals, Inc. Phosphorous-containing compounds with polymeric chains, and methods of making and using the same
US10624909B2 (en) 2015-12-11 2020-04-21 Eth Zurich Inositol derivatives for use in pathological crystallization
KR20180088411A (ko) * 2015-12-11 2018-08-03 에테하 쭈리히 병적인 결정화에서의 용도를 위한 이노시톨 유도체
US10487097B2 (en) 2015-12-11 2019-11-26 Eth Zurich 4,6-di-(O-thiophosphate)-inositol-1,2,3,5-tetra-O-sulfate for C. difficile infection
EP3386994B1 (fr) * 2015-12-11 2019-12-11 ETH Zürich 4,6-di- (o-thiophosphate) -inositol-1,2,3,5-tetra-o-sulfate pour infection c. difficile
WO2017098047A1 (fr) * 2015-12-11 2017-06-15 ETH Zürich Dérivés d'inositol à utiliser dans la cristallisation pathologique
EA037572B1 (ru) * 2015-12-11 2021-04-15 Этх Цюрих Производные инозитола для применения в патологической кристаллизации
US11028112B2 (en) 2015-12-11 2021-06-08 Eth Zurich Inositol derivatives for use in pathological crystallization
EP3848053A1 (fr) * 2015-12-11 2021-07-14 Universität Bern Dérivés d'inositol à utiliser dans la cristallisation pathologique
AU2016368547B2 (en) * 2015-12-11 2021-11-18 ETH Zürich Inositol derivatives for use in pathological crystallization
CN113788855A (zh) * 2015-12-11 2021-12-14 苏黎世联邦理工学院 用于病理性结晶的肌醇衍生物
US11707470B2 (en) 2015-12-11 2023-07-25 Eth Zurich Inositol derivatives for use in pathological crystallization
AU2022200542B2 (en) * 2015-12-11 2024-01-04 ETH Zürich Inositol derivatives for use in pathological crystallization
CN113788855B (zh) * 2015-12-11 2024-03-01 苏黎世联邦理工学院 用于病理性结晶的肌醇衍生物

Also Published As

Publication number Publication date
DE3740152A1 (de) 1988-06-09
SE8605063D0 (sv) 1986-11-26
JPS63198694A (ja) 1988-08-17
EP0269105B1 (fr) 1999-02-03
GR3030124T3 (en) 1999-07-30
DE3752250D1 (de) 1999-03-18
ES2130111T3 (es) 1999-07-01
GB2198135A (en) 1988-06-08
GB8727482D0 (en) 1987-12-23
CA1339660C (fr) 1998-02-03
AU8168287A (en) 1988-06-02
GB2198135B (en) 1991-07-31
GB8727483D0 (en) 1987-12-23
ATE176474T1 (de) 1999-02-15
US5157140A (en) 1992-10-20
DE3752250T2 (de) 1999-06-24
EP0269105A3 (fr) 1990-05-02
US5278332A (en) 1994-01-11
AU603158B2 (en) 1990-11-08
JP2528149B2 (ja) 1996-08-28

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